葡萄糖、胰岛素、胰岛素原、胰岛素抵抗和糖化血红蛋白的分位数依赖遗传力。
Quantile-Dependent Heritability of Glucose, Insulin, Proinsulin, Insulin Resistance, and Glycated Hemoglobin.
机构信息
Division of Molecular Biophysics & Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
出版信息
Lifestyle Genom. 2022;15(1):10-34. doi: 10.1159/000519382. Epub 2021 Dec 6.
BACKGROUND
"Quantile-dependent expressivity" is a dependence of genetic effects on whether the phenotype (e.g., insulin resistance) is high or low relative to its distribution.
METHODS
Quantile-specific offspring-parent regression slopes (βOP) were estimated by quantile regression for fasting glucose concentrations in 6,453 offspring-parent pairs from the Framingham Heart Study.
RESULTS
Quantile-specific heritability (h2), estimated by 2βOP/(1 + rspouse), increased 0.0045 ± 0.0007 (p = 8.8 × 10-14) for each 1% increment in the fasting glucose distribution, that is, h2 ± SE were 0.057 ± 0.021, 0.095 ± 0.024, 0.146 ± 0.019, 0.293 ± 0.038, and 0.456 ± 0.061 at the 10th, 25th, 50th, 75th, and 90th percentiles of the fasting glucose distribution, respectively. Significant increases in quantile-specific heritability were also suggested for fasting insulin (p = 1.2 × 10-6), homeostatic model assessment of insulin resistance (HOMA-IR, p = 5.3 × 10-5), insulin/glucose ratio (p = 3.9 × 10-5), proinsulin (p = 1.4 × 10-6), proinsulin/insulin ratio (p = 2.7 × 10-5), and glucose concentrations during a glucose tolerance test (p = 0.001), and their logarithmically transformed values.
DISCUSSION/CONCLUSION: These findings suggest alternative interpretations to precision medicine and gene-environment interactions, including alternative interpretation of reported synergisms between ACE, ADRB3, PPAR-γ2, and TNF-α polymorphisms and being born small for gestational age on adult insulin resistance (fetal origin theory), and gene-adiposity (APOE, ENPP1, GCKR, IGF2BP2, IL-6, IRS-1, KIAA0280, LEPR, MFHAS1, RETN, TCF7L2), gene-exercise (INS), gene-diet (ACSL1, ELOVL6, IRS-1, PLIN, S100A9), and gene-socioeconomic interactions.
背景
“分位数依赖表达性”是指遗传效应取决于表型（例如胰岛素抵抗）相对于其分布是高还是低。
方法
通过对弗雷明汉心脏研究中 6453 对父母-子女的空腹血糖浓度进行分位数回归，估计了分位数特异性的子女-父母回归斜率（βOP）。
结果
通过 2βOP/（1 + rspouse）估计的分位数特异性遗传度（h2），随着空腹血糖分布增加 1%，增加 0.0045±0.0007（p=8.8×10-14），即 h2±SE 分别为 0.057±0.021、0.095±0.024、0.146±0.019、0.293±0.038 和 0.456±0.061，分别在空腹血糖分布的第 10、25、50、75 和 90 百分位数。空腹胰岛素（p=1.2×10-6）、胰岛素抵抗稳态模型评估（HOMA-IR，p=5.3×10-5）、胰岛素/葡萄糖比值（p=3.9×10-5）、前胰岛素（p=1.4×10-6）、前胰岛素/胰岛素比值（p=2.7×10-5）和葡萄糖耐量试验期间的葡萄糖浓度（p=0.001），以及它们的对数转换值，也提示分位数特异性遗传度显著增加。
讨论/结论：这些发现为精准医学和基因-环境相互作用提供了替代解释，包括对 ACE、ADRB3、PPAR-γ2 和 TNF-α 多态性与出生时体重不足有关的报告协同作用和成年胰岛素抵抗（胎儿起源理论）以及基因肥胖（APOE、ENPP1、GCKR、IGF2BP2、IL-6、IRS-1、KIAA0280、LEPR、MFHAS1、RETN、TCF7L2）、基因运动（INS）、基因饮食（ACSL1、ELOVL6、IRS-1、PLIN、S100A9）和基因-社会经济相互作用的替代解释。
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